Summary Over 100,000 patients in the US currently await solid organ transplantation, with inadequate organs to save these patients from waitlist mortality. Safely expanding the donor pool, and optimally matching donors to the right recipient, is essential to transplantation. The overarching goal of the applicant is to guide clinical decision- making and policy in solid organ transplantation, particularly in the context of novel expansions such as HIV- infected donors and recipients, expanded criteria for living donation, and immunological incompatibility. This is a renewal proposal for a K24 Midcareer Investigator Award for Dorry Segev, MD, PhD, a transplant surgeon and epidemiologist at Johns Hopkins University who has published 422 papers and received 4 NIH R01 and 2 NIH U01 awards in his 12 years on faculty. The first 5 years of this K24 provided the protected time that Dr. Segev needed to mentor 11 residents, 16 medical students, 5 graduate students, and 14 junior faculty in an exciting, productive multidisciplinary environment; these mentees wrote 141 first-authored papers under Dr. Segev?s direct mentorship, and received 31 NIH/AHRQ grants and 13 foundation grants. This renewal will leverage carefully designed cohorts and data-driven tools that Dr. Segev has generated through NIH-funded studies, including (1) a linkage of national transplant donor and recipient registry data to insurance and pharmacy claims; (2) a longitudinal multicenter study of over 5500 living kidney donors; (3) multicenter study of long-term outcomes and survival benefit from incompatible live donor kidney transplantation, with granular HLA and antibody data on over 2000 recipients and their donors; and (4) a prospective multicenter study of frailty, health literacy, cognitive dysfunction, biomarkers, and other novel risk predictors, with over 5000 kidney transplant and 2000 liver transplant patients. In addition, this renewal will leverage two new U01-funded studies of HIV-to-HIV kidney and liver transplantation, including measurement of HIV-related complications, characterization of HIV-related kidney disease, measurement of HIV superinfection, and examination of the size and genetic composition of the latently infected HIV proviral population. These national data and large multicenter cohort studies provide rich substrate for ancillary studies by mentees, as well as many opportunities for advanced methodologic training. Specifically, the new aims of this K24 are: (1) to better understand survival benefit in HIV+ patients undergoing liver transplantation, using a novel linkage to identify patients with HIV on the LT waitlist by prescription fills of medications specific to HIV treatment; (2) to characterize long-term post-donation eGFR trajectories and associations with subsequent outcomes in living kidney donors; (3) to identify the appropriate treatment for sensitized patients in the recent era of deceased donor allocation and kidney exchange; and (4) to expand Dr. Segev?s capacity to mentor the next generation of clinician-scientists in solid organ transplantation.